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Staphylococcal Enterotoxin A Shapes Monocyte Transcription and Macrophage Polarization: Implications for Immune Responses in Infection and Inflammation

ABSTRACT: Staphylococcal enterotoxins (SE) crosslink the MHC-II on antigen-presenting cells (APC) with the T-cell receptor, inducing a polyclonal T-cell response. Although APCs are the initial targets of SE and are critical in shaping subsequent T-cell activation, the effects of SE on APC function remain poorly understood. This study investigates the immunomodulatory effects of staphylococcal enterotoxin A (SEA) on monocytes and their differentiation into monocyte-derived dendritic cells (moDC) or macrophages (MDM). Transcriptomic analyses of human monocytes via RNA sequencing revealed SEA-induced enrichment of gene pathways associated with inflammation, infection and dermatitis, effects that were amplified in the presence of T-cells. Phenotypic and functional characterization showed that SEA-primed monocytes differentiated into MDM with an altered polarization, deviating from classical M1/M2 pathways. SEA-primed MDM exhibited downregulayion of key markers including HLA-DR, CD80, CD86 and PD-L1. Functional assays demonstrated that SEA-primed MDM pushed hyperinflammatory T-cell responses, with significantly enhanced proliferation and IFN-γ secretion. In contrast, moDC retained robust antigen-presenting capabilities even upon SEA-priming. These findings provide mechanistic insights into SEA-mediated immune modulation, illustrating how SEA reprograms MDM functions and amplify proinflammatory T-cell responses. This advances our understanding of superantigen-driven immune interactions, offering a foundation for developing therapeutic strategies to mitigate superantigen-mediated immune conditions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE310786 | GEO | 2025/11/21

REPOSITORIES: GEO

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Project description:The species Staphylococcus (S.) aureus harbors 19 superantigen gene loci, six of which are located in the enterotoxin gene cluster (egc). While these egc superantigens are far more prevalent in clinical S. aureus isolates than non-egc superantigens, they are not a prominent cause of toxic shock. Moreover, neutralizing antibodies against egc superantigens are very rare, even among carriers of egc-positive S. aureus strains. In search of an explanation we have tested two non-exclusive hypotheses: 1) egc and non-egc superantigens have unique intrinsic properties and drive the immune system into different directions; 2) egc and non-egc-superantigens are released by S. aureus under different conditions, which shape the immune response. A comparison of three egc (SEI, SElM and SElO) and three non-egc superantigens (SEB, SElQ, TSST-1) revealed that both induced proliferation of human PBMC with comparable potency and elicited similar Th1/Th2-cytokine signatures. This was supported by gene expression analysis of PBMC stimulated with one representative superantigen from each group (SEI and SEB). They induced very similar transcriptional changes, especially of inflammation-associated gene networks, corresponding to a very strong Th1- and Th17-dominated immune response. In contrast, the regulation of superantigen release differed markedly between both superantigen groups. Egc-encoded proteins were secreted by S. aureus during exponential growth, while non-egc superantigens were released in the stationary phase. We conclude that the distinct biological behavior of egc and non-egc superantigens is not due to their intrinsic properties, which are very similar, but caused by their differential release by S. aureus. Experiment Overall Design: PBMCs from 3 healthy blood donors were purified and treated with Medium (control) and recombinant staphylococcal superantigens SEB and SEI. After 6 hours of treatment, total RNA was extracted and hybridized to Affymetrix GeneChip Arrays.

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Staphylococcal Enterotoxin A Shapes Monocyte Transcription and Macrophage Polarization: Implications for Immune Responses in Infection and Inflammation

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